`a2) Patent Application Publication co) Pub. No.: US 2006/0078602 Al
`(43) Pub. Date: Apr. 13, 2006
`
`Kanios
`
`US 20060078602A1
`
`(54)
`
`DEVICE FOR TRANSDERMAL
`ADMINISTRATION OF DRUGS INCLUDING
`ACRYLIC POLYMERS
`
`(75)
`
`Inventor: David Kanios, Miami, FL (US)
`
`Correspondence Address:
`DICKSTEIN SHAPIRO MORIN & OSHINSKY
`LLP
`2101 L Street, NW
`Washington, DC 20037 (US)
`
`(73)
`
`Assignee: Noven Pharmaceuticals, Inc.
`
`(21)
`
`Appl. No.:
`
`11/245,097
`
`(22)
`
`Filed:
`
`Oct. 7, 2005
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/616,860, filed on Oct.
`8, 2004.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`AGIK 9/70
`(52) US. C0.
`ccecscccssssessssssseesestnsssensteentssesenssseee 424/449
`
`(57)
`
`ABSTRACT
`
`A transdermal delivery system is provided where the drug
`delivery rates, onset and profiles of at least one active agent
`are controlled by selectively manipulating the monomeric
`make up of an acrylic-based polymerin the transdermal drug
`delivery system. The drug carrier composition may be
`comprised of (a) one or more acrylic-based polymers having
`one or more different monomers selected from the group
`consisting of hard and soft monomers; (b) one or more
`silicone-based polymers; and (c) one or moreactive agents
`where the device provides a desired solubility for the active
`agent and controls drug delivery rates, onset and profiles of
`at least one active agent.
`
`
`
`
`
`MYLAN- EXHIBIT 1007
`
`
`
`Patent Application Publication Apr. 13,2006 Sheet 1 of 2
`
`US 2006/0078602 Al
`
`HORMONE DRUGA(2 % Estrogen )
`
`10% 50%: Son / Hard Acryic Monomers
`tke 50% / 80%: Soft / Hard Acryic Monomers
`—O— 20% / 80% : Son / Hard Acrylic Monomers
`
`
`
`AverageFlux
`
`Figure 1
`
`HORMONEDRUGB( 2% Progestin)
`
`——H— 10% / 30% : Soft / Hard Acrylic Monomers
`—tk— _- 50% / 50% : Sof / Hard Acrylic Monomers
`—@— 20% / 80% : Soft / Hard Acryic Monomers
`
`(yofem2shry
`.
`
`
`
`
`
`AverageFiux(ug/emanr)
`
`
`
`Patent Application Publication Apr. 13,2006 Sheet 2 of 2
`
`US 2006/0078602 Al
`
`HORMONE DRUG C.( 2% Androgen )
`
`—Be— 50% / 50% : Soft / Hard Acrylic Monomers
`——@— 20% / 80% : Soft / Hard Acryic Monomers
`
`(tigfem2/hr)
`(ug/cm2/hr) 24
`
`
`
`AverageFlux
`
`
`
`AverageFlux
`
`Time (hrs)
`
`Figure 3
`
`AMINE DRUG A ( 6% Scopolamine)
`— 70% / 30% : Soft / Hard Acrylic Monomers
`
`50% / 50% : Soft / Hard Acrytic Monomers
`—@— 20% / 80% : Soft / Hard Acrytic Monomers
`
`Time (hrs)
`
`Figure 4
`
`
`
`US 2006/0078602 Al
`
`Apr. 13, 2006
`
`DEVICE FOR TRANSDERMAL ADMINISTRATION
`OF DRUGS INCLUDING ACRYLIC POLYMERS
`
`[0001] This application claims the benefit of provisional
`application 60/616,860 filed Oct. 8, 2004, which is hereby
`incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates generally to transdermal
`drug delivery systems, and more particularly to pharmaceu-
`tically acceptable adhesive matrix compositions. The inven-
`tion additionally relates to transdermal drug delivery sys-
`tems where the drug permeation, delivery rates and profiles
`can be selectively modulated within the transdermal drug
`delivery system.
`
`BACKGROUND OF THE INVENTION
`
`[0003] The use of transdermal drug delivery systems to
`topically administer an active agent is well known. These
`systems incorporate the active agent into a carrier compo-
`sition, such as a polymeric and/or pressure-sensitive adhe-
`sive composition, from which the active agent is delivered
`through the skin or mucosa ofthe user.
`
`drug
`transdermal
`[0004] Active-ingredient-containing
`delivery systems(“patches”) are essentially divided into two
`major technical systems: reservoir systems and matrix sys-
`tems. The present invention relates to matrix systems where
`the active ingredient(s) are embedded in a semi-solid matrix
`made up of a single polymer or a blend of polymers.
`
`[0005] Both types of devices employ a backing layer that
`forms the protective outer surface of the finished transder-
`mal system and which is exposed to the environment during
`use. A release liner or protective layer that forms the inner
`surface covers the polymeric adhesive which is employed
`for affixing the system to the skin or mucosaofa user. The
`release liner or protective layer is removed prior to appli-
`cation, exposing the adhesive, typically a pressure-sensitive
`adhesive.
`
`In the “classic” reservoir-type device, the active
`[0006]
`agent is typically dissolved or dispersed in a carrier to yield
`a non-finite carrier form, such as, for example, a fluid or gel.
`In the reservoir-type device, the active agent is generally
`kept separate from the adhesive. The device has a pocket or
`“reservoir” which physically serves to hold the active agent
`and carrier, and which is formedin or by a backing layer. A
`peripheral adhesive layer is then used to affix the device to
`the user.
`
`[0007] The reservoir-type devices have a numberofdis-
`advantages including a non-uniform drug release profile
`where a high dose of drug is initially released upon appli-
`cation to the user, often described as a “burst effect.” This
`burst or high initial release of drug then drops off after a
`period of time to a rate that necessary to achieve a thera-
`peutically effective amount. Drug delivery according to this
`profile is generally described as first order release.
`
`[0008] While classic reservoir-type devicesare still in use
`today,
`the term reservoir is being used interchangeably
`herein with matrix-type devices which still rely upon a
`separate adhesive means usedto affix the device to the user.
`
`In a matrix-type device, the active agent is dis-
`[0009]
`solved or dispersed in a carrier that typically is in a finite
`
`carrier form. The carrier form can be self-adhesive or
`non-adhesive. Non-adhesive matrix-type devices,
`that
`is,
`those whichstill rely on a separate adhesive meansto affix
`the device to the user, employ a drug permeable adhesive
`layer (often referred to as an “in-line adhesive” since the
`drug must pass through this layer) applied over the drug
`matrix carrier layer. To better control the release rate of the
`drug, the non-adhesive matrix-type devices often employ
`one or more additional drug permeable layers such as, for
`example, rate controlling membranes. The non-adhesive
`matrix-type devices often contain excipients, such as drug
`delivery enhancers, to help control the release rate. These
`devices are often referred to as multilayer or multilaminate.
`
`In a “monolithic” or “monolayer” matrix-type
`[0010]
`device, the active agent is typically solubilized or homog-
`enously blended in an adhesive carrier composition, typi-
`cally a pressure-sensitive adhesive or bioadhesive, which
`functions as both the drug carrier and the meansofaffixing
`the system to the skin or mucosa. Such devices, commonly
`referred to as drug-in-adhesive devices, are described, for
`example, in U.S. Pat. Nos. 4,994,267; 5,446,070; 5,474,783
`and 5,656,286, all of which are assigned to Noven Pharma-
`ceuticals,
`Inc., Miami, Fla. and herein incorporated by
`reference.
`
`[0011] While matrix-type devices, especially drug-in-ad-
`hesive devices, achieve more uniform and controlled drug
`deliver rates over longer periods of time, most transdermal
`systems remain subject to a higherinitial drug release than
`is required to achieve therapeutic efficacy. For many drugs
`and/or therapeutic situations, it would be advantageous to
`eliminate or suppress this higher initial release and achieve
`a “steady state” (zero order) release profile which uniformly
`delivers a therapeutically effective amount of drug over the
`extended duration of device’s desired use, preferably up to
`7 days or more.
`
`{0012] The highinitial blood level concentration ofcertain
`drugs may cause adverse or undesired effects, or create
`toxicity concerns, thereby limiting the use of transdermal
`administration. In other instances, the higher initial blood
`level concentration may reduce the amountof drug required
`for treatment to the point of risking under dosing, or the
`higherinitial blood level concentration may makeit imprac-
`tical to increase the duration of the device’s application
`while retaining therapeutic effectiveness. Reducing the fre-
`quency of replacing the transdermal drug delivery system
`would increase user compliance, reduce any lag or drop off
`in efficacious blood levels, and reduce the amount of drug
`required for treatment(also provided by reducing the higher
`initial blood level associated with the higher release rate).
`
`[0013] Drug concentration in transdermal delivery sys-
`tems can vary widely depending on the drug and polymers
`used. Low drug concentrations in the adhesive can result in
`difficulties in achieving an acceptable delivery rate of the
`medicament, preferably one approximating zero order kinet-
`ics. High drug concentrations, on the other hand, frequently
`affect the adhesion properties of the adhesives, and tend to
`promote unwanted crystallization.
`
`[0014] Simple diffusion models for permeation of drugs
`through the skin suggest that permeation rates are concen-
`tration dependent, that is, dependent on both the amount and
`the degree of drug within the pressure-sensitive adhesive
`composition. Some adhesives, such as, for example, poly-
`
`
`
`US 2006/0078602 Al
`
`Apr. 13, 2006
`
`acrylate adhesives have a high affinity for many drugs and
`thus tend to solubilize higher concentrations of drug than do,
`for example, rubber adhesives. However, the use of poly-
`acrylates alone as the adhesive is not without its drawbacks
`as polyacrylate adhesives, for example, may tend to cause
`skin irritation, especially when the transdermal device is
`used for extended periods of time.
`
`[0015] Therefore, despite the existence of many different
`types of transdermal delivery systems in the art,
`there
`remains a continuing need for improving the selective
`modulation of drug permeation, delivery rates and drug
`profiles in transdermal delivery systems.
`
`SUMMARY OF THE INVENTION
`
`[0016] Based upon the foregoing, it is an object of the
`present invention to overcome the limitations of the prior
`transdermal systems, and to provide a transdermal drug
`delivery system which allows selective modulation of drug
`permeation and delivery rates and profiles.
`
`[0017] Another object is to provide a transdermal system,
`which is simple and inexpensive to manufacture. The
`present invention provides a transdermal drug deliverysys-
`tem for the topical application of one or more active agents
`contained in one or more polymeric and/or adhesive carrier
`layers which is manufactured to optimize drug loading while
`providing desirable adhesion to skin or mucosa as well as
`providing modulation of the drug delivery andprofile.
`
`[0018] The invention is also directed to compositions and
`methods of controlling drug delivery rates, onset and pro-
`files of at least one active agent in a transdermal delivery
`system by selectively manipulating the monomeric make up
`of an acrylic-based polymerin the transdermaldrug delivery
`system. The drug carrier composition may be comprised of
`(a) one or more acrylic-based polymers having one or more
`different monomers selected from the group consisting of
`hard and soft monomers; (b) one or more silicone-based
`polymers having one or more silanol contents (capping)
`and/or resin to polymerratios and or a rubber; and (c) one
`or more active agents where the device provides a desired
`solubility for the active agent and controls drug delivery
`rates, onset and profiles of at least one active agent. Further
`manipulation of drug delivery, onset and profiles can be
`achieved by varying the concentrations of the drug in the
`drug-loaded carrier.
`
`[0019] Further embodiments of the invention include
`those described in the detailed description.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG.1 is a graphic representation of the effects on
`[0020]
`drug delivery, onset and profile of 17(-estradiol with dif-
`ferent proportions of hard and soft acrylic-based monomers
`in the pressure sensitive adhesives.
`
`FIG.2 is a graphic representation of the effects on
`[0021]
`drug delivery, onset and profile of norethindrone acetate
`with different proportions of hard and soft acrylic-based
`monomers in the pressure sensitive adhesives.
`
`FIG.3 is a graphic representation of the effects on
`[0022]
`drug delivery, onset and profile of testosterone with different
`proportions of hard and soft acrylic-based monomersin the
`pressure sensitive adhesives.
`
`[0023] FIG.4 is a graphic representation of the effects on
`drug delivery, onset and profile of scopolamine with differ-
`ent proportions of hard and soft acrylic-based monomers in
`the pressure sensitive adhesives.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`[0024] The foregoing and other objects are achieved by
`this invention which provides a transdermal drug delivery
`system to provide an adhesive matrix composition which
`effectively delivers drugs to a user over an extended period
`of time.
`
`[0025] Unless defined otherwise, all technical and scien-
`tific terms used herein have the same meaning as commonly
`understood by one of ordinary skill in the art to which the
`invention pertains.
`
`[0026] The invention relates to a pressure-sensitive adhe-
`sive composition comprising a single polymeror a blend of
`at least two polymers together with a drug. The blend ofat
`least two polymersis preferred andis herein referred to as
`a multiple polymer adhesive system. The term “blend”is
`used herein to mean that there is no, or substantially no,
`chemical
`reaction or cross-linking (other
`than simple
`H-bonding) between the different polymers in the multiple
`polymer adhesive system.
`
`[0027] As used herein, the term “pressure-sensitive adhe-
`sive”refers to a viscoelastic material which adheres almost
`instantaneously to most substrates with the application of
`very slight pressure and remains permanently tacky. A
`polymeris a pressure-sensitive adhesive within the meaning
`of the term as used herein if it has the properties of a
`pressure-sensitive adhesive perse or functions as a pressure-
`sensitive adhesive by admixture with tackifiers, plasticizers
`or other additives. The term pressure-sensitive adhesive also
`includes mixtures of different polymers and mixtures of
`polymers,
`such as polyisobutylenes
`(PIB) of different
`molecular weights, the resultant mixtures being a pressure-
`sensitive adhesive. In the last case, the polymers of lower
`molecular weight in the mixture are not considered to be
`“tackifiers,” the term “tackifier” being reserved for additives
`which differ other than in molecular weight from the poly-
`mers to which they are added.
`
`[0028] The term “topical” or “topically” is used herein in
`its conventional meaningas referring to direct contact with
`an anatomical site or surface area on a mammal including
`skin, teeth, nails and mucosa.
`
`[0029] The term “mucosa”as used herein means any moist
`anatomical membraneor surface on a mammalsuchasoral,
`buccal, vaginal, rectal, nasal or ophthalmic surfaces.
`
`[0030] The term “transdermal” as used herein means pas-
`sage into and/or through skin or mucosa for localized or
`systemic delivery of an active agent.
`
`[0031] The term “solubilized” is intended to mean that in
`the carrier composition there is an intimate dispersion or
`dissolution of the active agent at the crystalline, molecular
`or ionic level. As such,
`the solubilized active agent
`is
`considered herein to be in “non-crystallized” form when in
`the compositions of the present invention.
`
`[0032] The phrase “pharmaceutically acceptable flexible,
`finite” is intended to mean a solid form capable of conform-
`
`
`
`US 2006/0078602 Al
`
`Apr. 13, 2006
`
`ing to a surface to whichit is applied, and which is capable
`of maintaining the contact
`in such solid form so as to
`facilitate topical application without adverse physiological
`response, and without being appreciably decomposed by
`aqueous contact during use by a subject.
`
`[0033] The term “user”or “subject” is intended to include
`all warm-blooded mammals, preferably humans.
`
`[0034] The phrase “substantially zero-order” as used
`herein means transdermal delivery of an active agent at a
`release rate which is approximately constant once steady
`state is attained, typically within 12 to 24 hoursafter topical
`application. While variability in blood levels of active agent
`are contemplated within the scope of this meaning once
`steady state release is attained, the depletion rate of active
`agent over the duration of use should typically not exceed
`about 20% to about 25%.
`
`[0035] The term “active agent” (and its equivalents
`“agent,”“drug,’““medicament” and “pharmaceutical”)
`is
`intended to have the broadest meaning andincludesat least
`one of any therapeutic, prophylactic, pharmacological or
`physiological active substance, cosmetic and personal care
`preparations, and mixtures thereof, which is delivered to a
`mammal to produce a desired, usually beneficial, effect.
`Morespecifically, any active agent that is capable of pro-
`ducing a pharmacological response, localized or systemic,
`irrespective of whether therapeutic, diagnostic, cosmetic or
`prophylactic in nature,
`is within the contemplation of the
`invention. Also within the invention are such bioactive
`
`agents as pesticides, insect repellents, sun screens, cosmetic
`agents, etc. It should be noted that the drugs and/or bioactive
`agents may be used singularly or as a mixture of two or more
`such agents, and in amounts sufficient to prevent, cure,
`diagnose or treat a disease or other condition, as the case
`maybe.In the case of drugs, the drug can be inits free base
`or acid form, orin the form ofsalts, esters, amides, prodrugs,
`enantiomers or mixtures thereof, or any other pharmaco-
`logically acceptable derivatives, or as components of
`molecular complexes
`
`[0036] The drugis used in a “pharmacologically effective
`amount.” This term meansthat the concentration of the drug
`is such that in the composition it results in a therapeutic level
`of drug delivered over the term that the transdermal dosage
`form is to be used, preferably with zero order kinetics. Such
`delivery is dependent on a great numberofvariables includ-
`ing the drug, the time period for which the individual dosage
`unit is to be used, the flux rate of the drug from the system
`and a numberofother variables. The amount of drug needed
`can be experimentally determined based on the flux rate of
`the drug through the system and through the skin when used
`with and without enhancers. Having determinedtheflux rate
`needed, the transdermal delivery system is designed so that
`the release rate over the period of time of therapeutic use
`will be at least equal to the flux rate. Of course, the surface
`area of the transdermal delivery system also affects the
`delivery of the drug from the system.
`
`[0037] Drugs in general can be used in this invention.
`These drugs include those categories and species of drugs
`set forth on page ther-5 to ther-29 of the Merck Index, 11th
`Edition Merck & Co. Rahway, N.J. (1989).
`
`[0038] Exemplary of drugs that can be administered by the
`novel dermal drug delivery system include, but are not
`limited to:
`
`1. Central nervous system stimulants and agents
`[0039]
`such as Dextroamphetamine, Amphetamine, Methamphet-
`amine, D-Amphetamine, L-Amphetamine, D,L-Amphet-
`amine, Phentermine, Methylphenidate and Nicotine.
`
`such as
`and/or Anti-Migraine
`2. Analgesics
`[0040]
`Acetaminophen, Acetylsalicylic Acid, Buprenorphine,
`Codeine, I‘entanyl, Lisuride, Salicylic Acid derivatives and
`Sumatriptan.
`
`3. Androgen agents such as Fluoxymesterone,
`[0041]
`Methyl Testosterone, Oxymesterone, Oxymetholone, Test-
`osterone and Testosterone derivatives.
`
`4. Anesthetic agents such as Benzocaine, Bupivic-
`[0042]
`aine, Cocaine, Dibucaine, Dyclonine, Etidocaine, Lidocaine,
`Mepivacaine, Prilocaine, Procaine and Tetracaine.
`
`5. Anoretic agents such as Fenfluramine, Mazindol
`[0043]
`and Phentermine.
`
`6. Anti-Bacterial (antibiotic) agents including Ami-
`[0044]
`noglycosides, B-Lactams, Cephamycins, Macrolides, Peni-
`cillins, Polypeptides and Tetracyclines.
`
`7. Anti-Cancer agents such as Aminolevulinic Acid
`[0045]
`and Tamoxifen.
`
`8. Anti-Cholinergic agents such as Atropine, Euca-
`[0046]
`tropine and Scopolamine.
`
`9. Anti-Diabetic agents such as Glipizide, Gly-
`[0047]
`buride, Glypinamide and Insulins.
`
`10. Anti-Fungal agents such as Clortrimazole,
`[0048]
`Ketoconazole, Miconazole, Nystatin and Triacetin.
`
`11. Anti-Inflammatory and/or Corticoid agents
`[0049]
`such as Beclomethasone, Betamethasone, Betamethasone
`Diproprionate, Betamethasone Valerate, Corticosterone,
`Cortisone, Deoxycortocosterone and Deoxycortocosterone,
`Acetate, Diclofenac, Fenoprofen, Flucinolone, Fludrocorti-
`sone, Fluocinonide, Fluradrenolide, Flurbiprofen, Halcino-
`nide, Hydrocortisone, Ibuprofen, Ibuproxam, Indoprofen,
`Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphen-
`butazone, Piroxicam, Prednisolone, Prednisone, Suprofen
`and Triamcinolone Acetonide.
`
`[0050]
`
`12. Anti-Malarial agents such as Pyrimethamine.
`
`and/or Anti-Alzhiemer’s
`13. Anti-Parkinson’s
`{0051]
`such
`as Bromocriptine,
`1-Hydroxy-Tacrine,
`agents
`Levodopa, Lisaride Pergolide, Pramipexole, Ropinirole,
`Physostigimine, Tacrine Hydrochloride and Teruride.
`
`14. Anti-Psychotic and/or Anti-Anxiely agents
`[0052]
`such as Acetophenazine, Azapirones, Bromperidol, Chlor-
`proethazine, Chlorpromazine, Fluoxetine, Fluphenazine,
`Haloperidol,
`Loxapine, Mesoridazine, Molindone,
`Ondansetron, Perphenazine, Piperacetazine, Thiopropazate,
`Thioridazine, Thiothixene, Trifluoperazine and Triflupro-
`mazine.
`
`15. Anti-Ulcerative agents such as Enprostil and
`[0053]
`Misoprostol.
`
`16. Anti-Viral agents such as Acyclovir, Rimanta-
`[0054]
`dine and Vidarabine.
`
`17. Anxiolytic agents such as Buspirone, Benzo-
`[0055]
`diazepines such as Alprazolam, Chlordiazepoxide, Clon-
`
`
`
`US 2006/0078602 Al
`
`Apr. 13, 2006
`
`azepam, Clorazepate, Diazepam, Flurazepam, Halazepam,
`Lorazepam, Oxazepam, Oxazolam, Prazepam and Triaz-
`olam.
`
`18. B-Adrenergic agonist agents such as Albuterol,
`[0056]
`Carbuterol, Fenoterol, Metaproterenol, Rimiterol, Quinter-
`enol, Salmefamol, Soterenol, Tratoquinol, Terbutaline and
`Terbuterol.
`
`19. Bronchodilators such as Ephedrine derivatives
`[0057]
`including Epiniphrine and Isoproterenol, and Theophylline.
`
`20. Cardioactive agents such as Atenolol, Benzy-
`[0058]
`droflumethiazide, Bendroflumethiazide, Calcitonin, Capto-
`pril, Chlorothiazide, Clonidine, Dobutamine, Dopamine,
`Diltiazem, Enalapril, Enalaprilat, Gallopamil, Indometha-
`cin, Isosorbide Dinitrate and Mononitate, Nicardipine, Nife-
`dipine, Nitroglycerin, Papaverine, Prazosin, Procainamide,
`Propranolol, Prostaglandin E,, Quinidine Sulfate, Timolol,
`and Verapamil.
`
`21. a-Adrenergic agonist agents such as Phenyl-
`[0059]
`propanolamine.
`
`such as Acetylcholine,
`22. Cholinergic agents
`[0060]
`Arecoline, Bethanechol, Carbachol, Choline, Methacoline,
`Muscarine and Pilocarpine.
`
`23. Estrogens such as Conjugated Estrogenic Hor-
`[0061]
`mones, Equilenin, Equilin, Esterified Estrogens, Estradiol,
`17$-Estradiol, Estradiol Benzoate, 176-Estradiol Valerate,
`Estradiol 176-Cypionate, Estriol, Estrone, Estropipate, 17B-
`Ethiny] Estradiol and Mestranol.
`
`[0062]
`
`24. Muscle relaxants such as Baclofen.
`
`25. Narcotic antagonist agents such Nalmfene and
`[0063]
`Naloxone.
`
`26. Progestational agents such as Chlormadinone
`[0064]
`and Chlormadinone Acetate, Demegestone, Desogestrel,
`Dimethisterone, Dydrogesterone, Ethinylestrenol, Ethister-
`one, Ethynodiol and Ethynodiol Diacetate, Gestodene, 17a-
`Hydroxyprogesterone,
`Hydroxygesterone
`Caproate,
`Medroxyprogesterone and Medroxyprogesterone Acetate,
`Megestrol Acetate, Melengestrol, Norethindrone and Nore-
`thidrone Acetate, Norethynodrel, Norgesterone, Norgestrel,
`19-Norprogesterone, Progesterone, Promegestone andesters
`thereof. Free base forms of drugs which have a greater
`affinity for the acid (carboxyl) functional group in a carboxy]
`functional acrylic-based polymer are preferred in some
`applications.
`
`[0065] The drugs and mixtures thereof can be present in
`the composition in different forms, depending on which
`form yields the optimum delivery characteristics. Thus, in
`the case of drugs, the drug can be in its free base or acid
`form, or in the form of salts, esters, prodrugs, specific
`enantiomers or racemates, or any other pharmacologically
`acceptable derivatives, or as components of molecular com-
`plexes.
`
`[0066] Preferred drugs include crystalline drugs, such as,
`for example, estradiol, norethindrone acetate, testosterone,
`scopolamine
`
`[0067] As used herein, “therapeutically effective” means
`an amountof an active agent that is sufficient to achieve the
`desired local or systemic effect or result, such as to prevent,
`cure, diagnose, mitigateor treat a disease or condition, when
`
`applied topically over the duration of intended use. The
`amounts necessary are known in the literature or may be
`determined by methods knowninthe art, but typically range
`from about 0.1 mg to about 20,000 mg, and preferably from
`about 0.1 mg to about 1,000 mg, and most preferably from
`about 0.1 to about 500 mg per human adult or mammal of
`about 75 kg body weight per 24 hours.
`
`[0068] The amount of drug to be incorporated in the
`composition varies depending on the particular drug, the
`desired therapeutic effect, and the time span for which the
`device is to provide therapy. For most drugs, the passage of
`the drugs through the skin will be the rate-limiting step in
`delivery. Thus, the amount of drug andthe rate of release is
`typically selected so as to provide transdermal delivery
`characterized by a zero order time dependency for a pro-
`longed period of time. The minimum amountof drug in the
`system is selected based on the amount of drug which passes
`through the skin in the time span for which the deviceis to
`provide therapy. Normally, the amount of drug in the system
`can vary from about 0.1% to about 50%. However, the
`composition of this invention is particularly useful for drugs
`which are used in relatively low concentrations, especially
`0.3% to 30% of the total composition, more preferably from
`about 0.5% to about 15% of the total composition, most
`preferably from about 1% to about 10% of the total com-
`position.
`
`[0069] As used herein, the term “supersaturated” used in
`reference to the drug meansthat the amount of drug present
`is in excess of its solubility or dispersability in a multiple
`polymer adhesive system.
`
`[0070] As used herein “flux”is defined as the percutane-
`ous absorption of drugs through the skin, and is described by
`Fick’s first law of diffusion:
`
`J=-D(dC,,/dx),
`
`[0071] where J is the flux in g/cm?/sec, D is the diffusion
`coeflicient of the drug through the skin in em*/sec and
`dC,,/dx is the concentration gradient of the active agent
`across the skin or mucosa.
`
`[0072] The invention resulted from the discovery that the
`transdermal permeation rate of a drug from the pressure-
`sensitive adhesive system can be selectively modulated by
`adjusting the monomeric make up of the acrylic based
`polymerin the system. As used herein, the term “transder-
`mal permeation rate” means the rate of passage of the drug
`through the skin; which, as knownin the art, may or may not
`be affected by the rate of release of the drug from thecarrier.
`
`[0073] Solubility parameter, also referred to herein as
`“SP,” has been defined as the sum of all the intermolecular
`attractive forces, which are empirically related to the extent
`of mutual solubility of many chemical species. A general
`discussion of solubility parameters is found in an article by
`Vaughan, “Using Solubility Parameters in Cosmetics For-
`mulation,”/. Soc. Cosmet. Chem., Vol. 36, pages 319-333
`(1985).
`
`[0074] The present invention relates to a drug-in-adhesive
`system that is preferably formulated so that it is a pressure-
`sensitive adhesive at room temperature and has other desir-
`able characteristics for adhesives used in the transdermal
`drug delivery art. Such characteristics include good adher-
`ence to skin, ability to be peeled or otherwise removed
`
`
`
`US 2006/0078602 Al
`
`Apr. 13, 2006
`
`without substantial trauma to the skin, retention of tack with
`aging, etc. In general, the multiple polymer adhesive system
`should have a glass transition temperature (Tg), measured
`using a differential scanning calorimeter, of between about
`-70° C. and 70° C.
`
`[0075] The drug-in-adhesive system preferably includes at
`least one acrylic-based polymer, one polysiloxane or rubber
`and an active agent, where the monomeric make-up of the
`acrylic-based polymer modulates the drug delivery charac-
`teristics. In addition to selecting the monomeric makeup of
`the acrylic-based polymer, forming a blend of multiple
`polymersresults in an adhesive system having a character-
`istic “net solubility parameter,” the selection of which
`advantageously permits a selectable modulation of the deliv-
`ery rate of the drug by adjusting the solubility of the drug in
`the multiple polymer adhesive system.
`
`[0076] The term “acrylic-based” polymeris defined as any
`polyacrylate, polyacrylic, acrylate and acrylic polymer. The
`acrylic-based polymers can be any of the copolymers, ter-
`polymers, andthe like of various acrylic acids or esters. The
`acrylic-based polymers useful in practicing the invention are
`polymers of one or more monomers of acrylic acids and
`other copolymerizable monomers. The acrylic-based poly-
`mers also can include copolymers of alkyl acrylates and/or
`methacrylates and/or copolymerizable secondary mono-
`mers. The acrylic-based polymer may be functional or non
`functional.
`
`[0077] As used herein, “functionality” is broadly defined
`as a measure of the type and quantity of functional groups
`that a particular acrylic-based polymer has.
`
`Asused herein, “functional monomersor groups,”
`[0078]
`are monomer units in acrylic-based polymers which have
`reactive chemical groups which modify the acrylic-based
`polymers directly or provide sites for further reactions.
`Examples of functional groups include carboxyl, epoxy and
`hydroxy groups.
`
`[0079] As used herein “non-functional acrylic-based poly-
`mer’is defined as an acrylic-based polymer that has no or
`substantially no functional reactive moieties present in the
`acrylic. These are generally acrylic esters which can be
`copolymerized with other monomers which do not have
`functional groups, such as vinyl acetate.
`
`[0080] The term “carrier” as used herein refers to any
`non-aqueous material known in the art as suitable for
`transdermal drug delivery administration, and includes any
`polymeric material
`into which an active agent may be
`solubilized in combination or admixture with the other
`
`ingredients of the composition. The polymeric materials
`preferably comprise adhesives and, in particular, pressure-
`sensitive adhesives. The carrier material is typically used in
`an amount of about 40% to about 95%, and preferably from
`about 50% to about 80%, by weight based on the dry weight
`of the total carrier composition.
`
`‘lhe term “carrier composition” may also refer to
`[0081]
`enhancers, solvents, co-solvents and other types of addic-
`tives useful for facilitating transdermal drug delivery.
`
`[0082] The acrylic-based polymer accordingto the present
`invention is preferably polymerized from at least two mono-
`mers. The first monomer includes at least one soft acrylic
`monomer and the second monomerincludes at least one
`
`hard acrylic monomer.
`
`Asused herein, the term “soft acrylic monomer”is
`[0083]
`intended to refer to a monomer which is present in the
`transdermal drug delivery system as one monomerin the
`acrylic pressure-sensitive adhesive that hasa glass transition
`temperature (T,) from about -70° C. to about -10° C., more
`preferably from about -60° C. to about -20° C., and most
`preferably from about -60° C.
`to about -24° C. Some
`examples of soft acrylic monomers include: 2-ethyl hexyl
`acrylate,
`isobutyl acrylate, ethyl acrylate, butyl acrylate,
`dodecyl methacrylate, 2-ethylhexyl methacrylate, 2-ethoxy-
`ethyl acrylate, isopropyl acrylate, and 2-methoxyethyl acry-
`late.
`
`[0084] As used herein, the term “hard acrylic monomer”is
`intended to refer to a monomer which is present in the
`transdermal drug delivery system as a one monomerin the
`acrylic pressure sensitive adhesivethat has a glass transition
`temperature (T,) from about -5° C. to about 120° C., more
`preferably from about 10° C. to about 120° C., and most
`preferably from about 10° C.
`to about 105° C. Some
`examples of hard acrylic monomers include: methacrylate,
`N-butyl acrylate, acrylic acid, butyl methacrylate, ethyl
`methacrylate, methyl methacrylate, hexyl methacrylate, and
`methyl acrylate.
`
`[0085] Values for the glass transition temperatures are
`based uponliterature values most commonly reported for the
`homopolymers of the corresponding monomers.
`
`[0086] The amountof soft acrylic monomer that makes up
`the acrylic based polymeraccordingto the present invention
`ranges from about 20 to about 70% by weight of the acrylic
`based polymer. The